In recent years there has been a growing realization that immune responses play a central role in cancer biology by eliminating many tumours at a very early stage and keeping those that avoid total elimination in a state of equilibrium, sometimes for many years (Dunn et al., Annu Rev Immunol 2004; 22:329-360). The eventual escape from this equilibrium phase with clinical manifestation of the disease is associated with dysregulated immune responses, manifesting, for example, as chronic inflammation or immune tolerance. The strong and increasing evidence that the immune system is critically involved in the development, structural nature and progression of cancer has led to renewed interest in immunotherapeutic strategies for treatment of this class of diseases. To date, most attempts to develop such strategies have been based on the use of antigens derived from the patient's own tumour or from tumour cell lines and the transfer of ex-vivo expanded populations of tumour antigen-specific cytotoxic cells and antigen-presenting cells.
Cancer has been associated with inflammation since 1863, when Rudolf Virchow discovered leucocytes in neoplastic tissues and so made the first connection between inflammation and cancer (Balkwill et al., Lancet 2001; 357:539-545). Since then, chronic inflammation has been deemed to be a risk factor for cancer. These reports demonstrate that an inflammatory environment supports tumour development and is consistent with that observed at tumour sites. However, the relationship of cancer with inflammation is not limited to the onset of the disease due to chronic inflammation. Schwartsburd (Cancer and Metastasis reviews 2003; 22:95-102) proposed that chronic inflammation occurs due to tumour environment stress and that this generates a shield from the immune system. It has been recently demonstrated that the tumour microenvironment resembles an inflammation site, with significant support for tumour progression, through chemokines, cytokines, lymphocytes and macrophages which contribute to both the neovascularisation and vasal dilation for increased blood flow, the immunosuppression associated with the malignant disease, and tumour metastasis. Furthermore, this inflammation-site tumour-generated microenvironment, apart from its significant role in protection from the immune system and promotion of cancer progression, has an adverse effect on the success of current cancer treatments. Indeed, it has been found that the inflammatory response in cancer can compromise the pharmacodynamics of chemotherapeutic agents (Slaviero et al., Lancet Oncol 2003; 4:224-32).
Moreover, metastatic cancer cells leave the tumour as microcolonies, containing lymphocytes and platelets as well as tumour cells. Inflammation continues to play a role at metastatic sites by creating a cytokine milieu conducive to tumour growth.
Immune homeostasis consists of a tightly regulated interplay of pro- and anti-inflammatory signals. For example, loss of the anti-inflammatory signals leads to chronic inflammation and proliferative signalling. Interestingly, cytokines that both promote and suppress proliferation of the tumour cells are produced at the tumour site. As in the case of cancer initiation, it is the imbalance between the effects of these various processes that results in tumour promotion.
It is believed that, to treat cancer, the most effective type of immune response is of a Type 1, which favours the induction of CD4+Th1 cellular responses, and of CD8+CTL responses. In the context of cancer vaccines, many immune stimulants are used, which promote the development of Th1 responses and are thought to inhibit the production of a Th2 response. For example, BCG (bacillus Calmette-Guerin) an attenuated strain of M. bovis developed as a vaccine against M. tuberculosis infection is also used for treatment of various other conditions, such as bladder carcinoma and cutaneous melanoma. Intravesical instillation of BCG for superficial transitional cell carcinoma of the bladder is currently considered a first-line treatment for this disease. Although serious complications with intravesical BCG are uncommon, these can occur in individuals and can range from local symptoms to hepatitis, pneumonitis, sepsis, and death. SRL-172 is a heat-killed preparation of Mycobacterium vaccae, a member of the same genus as bacille Calmette-Guerin (BCG) but with additional immunological properties, as it induces both immunoregulation and Type 1 enhancing effects.
To date, a major barrier to attempts to develop effective immunotherapy for cancer has been an inability to break immunosuppression at the cancer site and restore normal networks of immune reactivity. The physiological approach of immunotherapy is to normalize the immune reactivity so that the endogenous tumour antigens would be recognized and effective cytolytic responses would be developed against cells bearing these antigens.
Anti-cancer immune responses accompanying the action of chemo- and radiotherapy have been reviewed in detail and show that such responses are indispensible to therapeutic success by eliminating residual cancer cells and maintaining micrometastases in a state of dormancy (Zitvogel et al., J Clin Invest 2008; 118:1991-2001). However, this reference makes it clear that there is no simple immunotherapeutic strategy available for consistently enhancing such immune responses. Likewise, it has been suggested that radiofrequency ablation of tumours, mainly hepatic, could, by providing an accessible and immunogenic source of tumour antigens, synergise with active immunotherapy, if such immunotherapy were developed (Fagnoni et al., Front Biosci 2008; 13:369-381).
There is evidence that therapeutic procedures that induce certain forms of cancer cell death also lead to surface expression or release of tumour antigens. There are three main types of cell death (Tesniere et al., Cell Death Differ 2008; 15:3-12): apoptosis (type 1), autophagy (type 2) and necrosis (type 3). Apoptosis, or programmed cell death, is a common and regular occurring phenomenon essential for tissue remodelling, especially in utero but also throughout life. It is characterized by DNA fragmentation in the nucleus and condensation of the cytoplasm to form ‘apoptotic bodies’ which are engulfed and digested by phagocytic cells. In autophagy, cell organelles and cytoplasm are sequestered in vacuoles which are extruded from the cell. Although this provides a means of survival for cells in adverse nutritional conditions or other stressful situations, excess autophagy results in cell death. Necrosis is a ‘cruder’ process characterized by damage to intracellular organelles and cell swelling, resulting in rupture of the cell membrane and release of intracellular material.
It has widely been held that apoptosis is immunologically ‘silent’, as would be expected from its physiological role and by the finding that local inflammation is suppressed by the release of anti-inflammatory mediators. More recently it has been suggested that there are different forms of apoptosis and some are immunogenic (Zitvogel et al., Adv Immunol 2004; 84: 131-179). The relationship of autophagy to immunogenicity is poorly understood but necrosis certainly releases many antigens, although in progressive cancers, such necrosis might also enhance the chronic inflammation that favours tumour growth (Vakkila et al., Nat Rev Immunol 2004; 4: 641-648; Zeh et al., J Immunother 2005; 28:1-9). In this sense, a cancer resembles a chronically inflamed wound that does not heal (Dvorak. N Engl J Med 1986; 315:1650-1659).
Efforts have been made in the art to provide combined ablative and chemotherapies for the treatment of tumours. WO2000064476 and US20050187207 disclose the use of an immunoadjuvant in combination with photodynamic therapy for the treatment of metastatic tumours. These documents disclose that the immunoadjuvant comprises mycobacterial cell wall skeletons and de-3-O-acylated lipid A and is administered by injection into the tumour. Castano et al. (Nat Rev Cancers 2006; 6:535), Korbelik et al. (J Photochem and Photobiol 1998; 44:151) and Korbelik et al. (J Photochem and Photobiol, 2001; 73:403) also disclose the treatment of tumours using a combination of photodynamic therapy and the administration of mycobacterial cell wall extract as an immunoadjuvant. Mycobacterial cell walls contain compounds such as trehalose dimycolate and muramyl dipeptide which are known immunostimulators. The mycobacterial cell wall extracts used in the prior art combination therapies also elicit pro-inflammatory cytokines, reactive nitrogen species and recruit leukocytes which are associated with pathology including weight loss due to TNF-α, mediated cachexia, with associated lipidemia, hypoglycaemia and peritonitis with ischemic and hemorrhagic lesions in the GI tract. The prior art combination therapies may therefore exacerbate the inflammatory response and have severe side effects.
An aim of the present invention is to solve the problems associated with the combination therapies for tumours observed in the prior art and, specifically, to provide a treatment for secondary cancers formed by metastasis of a primary cancer away from the site of the primary cancer.